Pediatric Huntington Disease Brains Have Distinct Morphologic and Metabolic Traits: the RAREST-JHD Study.

BACKGROUND: Pediatric-onset Huntington's disease (POHD) exhibits a phenotype different from adult-onset HD (AOHD), with hypokinetic movement disorders (eg, rigidity, bradykinesia, and dystonia) rather than chorea typical of AOHD. OBJECTIVES: The aim was to identify pathophysiology-based biomarkers specific to POHD (≥60 CAG repeats). METHODS: Simultaneous hybrid imaging using [18F]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography plus magnetic resonance imaging (FDG-PET/MRI) and clinical assessment using standardized Huntington's disease (HD) scales were employed. Exploratory longitudinal analyses were also performed. RESULTS: Striatal volume loss was remarkable and more severe in POHD (n = 5) than in AOHD (n = 14). Widespread, significantly altered glucose metabolism occurred in several different POHD cortical areas and thalamus, but not AOHD cortex, consistent with differences in clinical progression. CONCLUSIONS: POHD patients' brains exhibited distinct morphologic and metabolic traits compared to AOHD patients' brains, with longitudinal changes mirroring clinical progression. Hybrid FDG-PET/MRI highlighted a variable regional brain dysfunction in vivo, as a biological consequence of highly expanded CAG repeats. Findings provide further evidence that POHD is a distinct disease from AOHD.

Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise.

Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington's disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions.

Virtual reality tolerability, sense of presence and usability in Huntington disease: a pilot study.

INTRODUCTION: Several studies demonstrated the utility of immersive virtual reality (VR) as a complementary approach to conventional therapy for improving motor, psychological and cognitive impairment in some pathological conditions. Our pilot study aims to evaluate for the first time: 1) sense of presence, tolerability and usability of VR immersive experience in patients with early stages of Huntington disease (eHDp) compared to healthy controls (HC); 2) correlation between the use of technology/cybersickness and the variables of presence/usability; 3) correlation between clinical characteristics (genetic, motor, functional and cognitive) and VR's variables. METHOD: We recruited 10 eHDp and 10 age, gender and education matched HC. Participants completed questionnaires about sense of presence, usability, tolerability and technology use profile. Subjects were exposed to different VR scenarios from a first-person perspective through a standalone VR headset. RESULTS: Our results showed no significant statistical difference between eHDp and HC for the sense of presence (p=0.910), usability (p=0.744) and tolerability (p=0.730) during the VR experience. Familiarity with the use of technology was also comparable between groups (p=0.676). Regarding correlations in eHDp group, our results showed no correlations between use of technology/tolerability and the sense of presence/usability. Moreover, clinical characteristics of eHDp (genetic, motor, functional and cognitive scores) did not influence the sense of presence, tolerability and usability. CONCLUSION: Our research presents preliminary evidence for the applicability of VR in eHDp. These results open up the possibility to explore future applications of this methodology in rehabilitation (i.e., cognitive training, physiotherapy), diagnosis and psychological support in Huntington disease patients.

Development of the Huntington Support App (HD-eHelp study): a human-centered and co-design approach.

Introduction: eHealth seems promising in addressing challenges in the provision of care for Huntington's disease (HD) across Europe. By harnessing information and communication technologies, eHealth can partially relocate care from specialized centers to the patients' home, thereby increasing the availability and accessibility of specialty care services beyond regional borders. Previous research on eHealth (development) in HD is however limited, especially when it comes to including eHealth services specifically designed together with HD gene expansion carriers (HDGECs) and their partners to fit their needs and expectations. Methods: This article describes the qualitative human-centered design process and first evaluations of the Huntington Support App prototype: a web-app aimed to support the quality of life (QoL) of HDGECs and their partners in Europe. Prospective end-users, i.e., HDGECs, their partners, and healthcare providers (HCPs), from different countries were involved throughout the development process. Through interviews, we captured people's experiences with the disease, quality of life (QoL), and eHealth. We translated their stories into design directions that were further co-designed and subsequently evaluated with the user groups. Results: The resulting prototype centralizes clear and reliable information on the disease, HD-related news and events, as well as direct contact possibilities with HCPs via an online walk-in hour or by scheduling an appointment. The app's prototype was positively received and rated as (very) appealing, pleasant, easy to use and helpful by both HDGECs and partners. Discussion: By involving end-users in every step, we developed a healthcare app that meets relevant needs of individuals affected by HD and therefore may lead to high adoption and retention rates. As a result, the app provides low-threshold access to reliable information and specialized care for HD in Europe. A description of the Huntington Support App as well as implications for further development of the app's prototype are provided.

Beyond CAG Repeats: The Multifaceted Role of Genetics in Huntington Disease.

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin (HTT) gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the HTT gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders.

Clinical Review of Juvenile Huntington's Disease.

 Juvenile Huntington's disease (JHD) is rare. In the first decade of life speech difficulties, rigidity, and dystonia are common clinical motor symptoms, whereas onset in the second decade motor symptoms may sometimes resemble adult-onset Huntington's disease (AOHD). Cognitive decline is mostly detected by declining school performances. Behavioral symptoms in general do not differ from AOHD but may be confused with autism spectrum disorder or attention deficit hyperactivity disorder and lead to misdiagnosis and/or diagnostic delay. JHD specific features are epilepsy, ataxia, spasticity, pain, itching, and possibly liver steatosis. Disease progression of JHD is faster compared to AOHD and the disease duration is shorter, particularly in case of higher CAG repeat lengths. The diagnosis is based on clinical judgement in combination with a positive family history and/or DNA analysis after careful consideration. Repeat length in JHD is usually > 55 and caused by anticipation, usually via paternal transmission. There are no pharmacological and multidisciplinary guidelines for JHD treatment. Future perspectives for earlier diagnosis are better diagnostic markers such as qualitative MRI and neurofilament light in serum.

Prodromal Cognitive Changes as a Prognostic Indicator of Forthcoming Huntington's Disease Severity: A Retrospective Longitudinal Study.

BACKGROUND: Cognitive changes in Huntington's disease (HD) precede motor manifestations. ENROLL-HD platform includes four cognitive measures of information processing speed (IPS). Our group is eager to seek clinical markers in the life stage that is as close as possible to the age of onset (ie, the so called prodromal HD phase) because this is the best time for therapeutic interventions. OBJECTIVES: Our study aimed to test whether cognitive scores in prodromal ENROLL-HD mutation carriers show the potential to predict the severity of motor and behavioral changes once HD became fully manifested. METHODS: From the global ENROLL-HD cohort of 21,343 participants, we first selected a premanifest Cohort#1 (ie, subjects with Total Motor Score (TMS) <10 and Diagnostic Confidence Level (DCL) <4, N = 1.222). From this cohort, we then focused on a prodromal Cohort#2 of subjects who were ascertained to phenoconvert into manifest HD at follow-up visits (ie, subjects from 6 ≤ TMS≤9 and DCL <4 to TMS≥10 and DCL = 4, n = 206). RESULTS: The main results of our study showed that low IPS before phenoconversion in Cohort#2 predicted the severity of motor and behavioral manifestations. By combining the four IPS cognitive measures (eg, the Categorical Verbal Fluency Test; Stroop Color Naming Test; Stroop Word Reading; Symbol Digit Modalities Test), we generated a Composite Cognition Score (CCS). The lower the CCS score the higher the TMS and the apathy scores in the same longitudinally followed-up patients after phenoconversion. CONCLUSIONS: CCS might represent a clinical instrument to predict the prognosis of mutation carriers who are close to manifesting HD.

Validity, diagnostics and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

BACKGROUND: This study is aimed at assessing the clinimetric properties and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in patients with Huntington's disease (HD). METHODS: N = 39 motor-manifest HD patients, N = 74 Parkinson's disease (PD) patients and N = 92 matched HCs were administered the MoCA. HD patients further underwent the Unified Huntington's Disease Rating Scale (UHDRS), self-report questionnaires for anxiety and depression and a battery of first- and second-level cognitive tests. Construct validity was tested against cognitive and behavioural/psychiatric measures, whereas ecological validity against motor-functional subscales of the UHDRS. Sensitivity to disease severity was tested, via a logistic regression, by exploring whether the MoCA discriminated between patients in Shoulson-Fahn stage ≤ 2 vs. > 2. The same analysis was employed to test its ability to discriminate HD patients from HCs and PD patients. RESULTS: The MoCA converged towards cognitive and behavioural measures but diverged from psychiatric ones, being also associated with motor/functional measures from the UHDRS. In identifying patients with cognitive impairment, adjusted MoCA scores were highly accurate (AUC = .92), yielding optimal diagnostics at the cut-off of < 19.945 (J = .78). The MoCA was able to discriminate patients in the middle-to-advanced from those in the early-to-middle stages of the disease (p = .037), as well as to differentiate HD patients from both HCs (p < .001) and PD patients (p < .001). CONCLUSIONS: The MoCA is a valid, diagnostically sound and feasible cognitive screener in motor-manifest HD patients, whose adoption is thus encouraged in clinical practice and research.

GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study.

BACKGROUND: Paediatric Huntington disease with highly expanded mutations (HE-PHD; >80 CAG repeats) presents atypically, compared to adult-onset Huntington disease (AOHD), with neurodevelopmental delay, epilepsy, abnormal brain glucose metabolism, early striatal damage, and reduced lifespan. Since genetic GLUT-1 deficiency syndrome shows a symptom spectrum similar to HE-PHD, we investigated the potential role of the two main glucose transporters, GLUT-1 and GLUT-3, in HE-PHD. METHODS: We compared GLUT-1 and GLUT-3 protein expression in HE-PHD, juvenile-onset (JOHD), and AOHD brains (n = 2; n = 3; n = 6) and periphery (n = 3; n = 2; n = 2) versus healthy adult controls (n = 6; n = 6). We also investigated mitochondrial complexes and hexokinase-II protein expression. FINDINGS: GLUT-1 and GLUT-3 expression were significantly lower in HE-PHD frontal cortex (p = 0.009, 95% [CI 13.4, 14.7]; p = 0.017, 95% [CI 14.2, 14.5]) versus controls. In fibroblasts, GLUT-1 and GLUT-3 expression were lower compared to controls (p < 0.0001, 95% [CI 0.91, 1.09]; p = 0.046, 95% [CI 0.93, 1.07]). In the frontal cortex, this occurred without evidence of extensive neuronal degeneration. Patients with HE-PHD had deregulated mitochondrial complex expression, particularly complexes II-III, levels of which were lower in frontal cortex versus controls (p = 0.027, 95% [CI 17.1, 17.6]; p = 0.002, 95% CI [16.6, 16.9]) and patients with AOHD (p = 0.052, 95% [CI 17.0, 17.6]; p = 0.002, 95% [CI 16.6, 16.7]). Hexokinase-II expression was also lower in HE-PHD frontal cortex and striatum versus controls (p = 0.010, 95% [CI 17.8, 18.2]; p = 0.045, 95% [CI 18.6, 18.7]) and in frontal cortex versus patients with AOHD (p = 0.013, 95% [CI 17.7, 18.1]). Expression JOHD levels were consistently different to those of HE-PHD but similar to those of AOHD. INTERPRETATION: Our data suggest a dysfunctional hypometabolic state occurring specifically in paediatric Huntington disease brains. FUNDING: '5 × 1000' Personal Income Tax donation to LIRH Foundation; Italian Ministry of HealthRC2301MH04 and RF-2016-02364123 to CSS.

The validation of the Italian version of multiple sclerosis neuropsychological screening questionnaire in Huntington's disease.

INTRODUCTION: Multiple sclerosis neuropsychological questionnaire (MSNQ) is a brief questionnaire useful for screening patient's and informant's self-perception of cognitive dysfunctions in daily life activities. Our study aims to evaluate the MSNQ validity in Huntington's disease (HD) mutation carriers and to correlate MSNQ scores with neurological, cognitive, and behavioral variables. METHODS: The study was conducted on a sample of 107 subjects from presymptomatic to the middle stage of HD recruited at LIRH Foundation and C.S.S. Mendel Institute in Rome. Unified Huntington's Disease Rating Scale (UHDRS), an internationally standardized and validated scale, was used to evaluate motor, functional cognitive, and behavioral domains. RESULTS: Our results showed that in HD subjects, MSNQ has a unidimensional factor structure. Correlational analyses indicated a good correlation between the MSNQ-patient version (MSNQ-p) and clinical variables, specifically with cognitive dysfunction and behavioral alterations. Moreover, higher scores in MSNQ-p were associated with higher motor disease and functional impairment showing that patients in advanced stage of HD perceive a greater cognitive impairment. These results confirm the questionnaire's reliability. CONCLUSIONS: The present study demonstrates the validity and adaptability of MSNQ in the HD population proposing it as a cognitive tool during routine clinical follow-ups, although further research is needed to determine an optimal cut-off score for this measure.

Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease: a comparison of assessment instruments.

BACKGROUND: Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. METHODS: We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. RESULTS: The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. CONCLUSION: The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia.

Economic burden of Huntington disease in Europe and the USA: Results from the Huntington's Disease Burden of Illness study.

BACKGROUND AND PURPOSE: The prevalence of Huntington disease (HD) has increased over time; however, there is a lack of up-to-date evidence documenting the economic burden of HD by disease stage. This study provides an estimate of the annual direct medical, nonmedical, and indirect costs associated with HD from participants in the Huntington's Disease Burden of Illness (HDBOI) study in five European countries and the USA. METHODS: The HDBOI is a retrospective, cross-sectional study. Data collection was conducted between September 2020 and May 2021. Participants were recruited by their HD-treating physicians and categorized as early stage (ES), mid stage (MS), or advanced stage (AS) HD. Data were collected via three questionnaires: a case report form, completed by physicians who collected health care resource use associated with HD to compute direct medical cost, and optional patient and caregiver questionnaires, which included information used to compute nondirect medical and indirect costs. Country-specific unit cost sources were used. RESULTS: HDBOI cost estimates were €12,663 (n = 2094) for direct medical costs, €2984 (n = 359) for nondirect medical costs, and €47,576 (n = 436) for indirect costs. Costs are higher in patients who are at later stages of disease; for example, direct medical costs estimates were €9220 (n = 846), €11,885 (n = 701), and €18,985 (n = 547) for ES, MS, and AS, respectively. Similar trends were observed for nondirect and indirect costs. Costs show large variations between patients and countries. CONCLUSIONS: Cost estimates from the HDBOI study show that people with HD and their caregivers bear a large economic burden that increases as disease progresses.

Diagnostic properties of the Frontal Assessment Battery (FAB) in Huntington's disease.

Background: This study aimed at assessing the diagnostic properties of the Frontal Assessment Battery (FAB) as to its capability to (1) discriminate healthy controls (HCs) from patients with Huntington's disease (HD) and (2) identify cognitive impairment in this population. Materials: Thirty-eight consecutive HD patients were compared to 73 HCs on the FAB. Patients further underwent the Montreal Cognitive Assessment (MoCA) and the Unified Huntington's Disease Rating Scale (UHDRS). Receiver-operating characteristics (ROC) analyses were run to assess both intrinsic-i.e., sensitivity (Se) and specificity (Sp), and post-test diagnostics, positive and negative predictive values (PPV; NPV) and likelihood ratios (LR+; LR-), of the FAB both in a case-control setting and to identify, within the patient cohort, cognitive impairment (operationalized as a below-cut-off MoCA score). In patients, its diagnostic accuracy was also compared to that of the cognitive section of the UHDRS (UHDRS-II). Results: The FAB and UHDRS-II were completed by 100 and 89.5% of patients, respectively. The FAB showed optimal case-control discrimination accuracy (AUC = 0.86-0.88) and diagnostic properties (Se = 0.68-0.74; Sp = 0.88-0.9; PPV = 0.74-0.8; NPV = 0.84-0.87; LR+ = 5.6-7.68; LR- = 0.36-0.29), performing even better (AUC = 0.9-0.91) at identifying cognitive impairment among patients (Se = 0.73-1; Sp = 0.86-0.71; PPV = 0.79-0.71; NPV = 0.82-1; LR+ =5.13-3.5; LR- = 0.31-0) and comparably to the UHDRS-II (89% vs. 85% of accuracy, respectively; p = 0.46). Discussion: In HD patients, the FAB is highly feasible for cognitive screening aims, being also featured by optimal intrinsic/post-test diagnostics within both case-control and case-finding settings.

Semiology and determinants of apathy across neurodegenerative motor disorders: A comparison between amyotrophic lateral sclerosis, Parkinson's and Huntington's disease.

Background: The semiology and determinants of apathy are largely unknown across amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD), due to both motor and non-motor confounders. This study thus aimed at (1) profiling apathy in ALS, PD, and HD and (2) exploring its clinical determinants. Materials: Consecutive ALS (N = 99), PD (N = 73), and HD (N = 25) patients underwent a motor-free assessment of apathy (Dimensional Apathy Scale, DAS), global cognition, anxiety and depression. Function was assessed through disease-specific scales. The DAS was also completed by N = 101 healthy controls (HCs). Between-group comparisons on DAS scores were implemented by covarying for all applicable confounders. Predictive models on DAS scores were built through multiple, stepwise regressions. Results: Parkinson's disease and HD, but not ALS, patients were more apathetic than HCs-with HD patients also selectively showing lower initiation and poorer goal-directed planning than HCs. Higher apathetic features were detected in PD and HD as compared to ALS. Education was a protective factor against apathy in ALS. Anxiety was a risk factor for global apathy in ALS, HD, and to a lesser extent, in PD, whereas, protective only toward affective disintegration in PD and ALS. Cognitive inefficiency was a risk factor toward apathy in both PD and ALS. Depression was a risk factor for executive-related apathy in PD. Discussion: This study provides unprecedented insights into the heterogeneous semiology and determinants of apathy across ALS, PD, and HD via the DAS, in turn informing clinical practice and research.

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington's Disease.

Whether as a cause or a symptom, RNA transcription is recurrently altered in pathologic conditions. This is also true for non-coding RNAs, with regulatory functions in a variety of processes such as differentiation, cell identity and metabolism. In line with their increasingly recognized roles in cellular pathways, RNAs are also currently evaluated as possible disease biomarkers. They could be informative not only to follow disease progression and assess treatment efficacy in clinics, but also to aid in the development of new therapeutic approaches. This is especially important for neurological and genetic disorders, where the administration of appropriate treatment during the disease prodromal stage could significantly delay, if not halt, disease progression. In this review we focus on the current status of biomarkers in Huntington's Disease (HD), a fatal hereditary and degenerative disease condition. First, we revise the sources and type of wet biomarkers currently in use. Then, we explore the feasibility of different RNA types (miRNA, ncRNA, circRNA) as possible biomarker candidates, discussing potential advantages, disadvantages, sources of origin and the ongoing investigations on this topic.

Sleep Quality and Related Clinical Manifestations in Huntington Disease.

(1) Background: Sleep patterns are frequently disrupted in neurodegenerative disorders such as Huntington disease (HD); however, they are still poorly understood, especially their association with clinic features. Our study aimed to explore potential correlations between sleep features and motor, cognitive, behavioural and functional changes in manifest HD subjects. (2) Methods: We enrolled 42 patients who were assessed by the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) questionnaires; clinical features were evaluated by the validated ENROLL-HD platform assay, including the Unified Huntington's Disease Rating Scale (UHDRS) and the Problem Behaviours Assessment Short Form (PBA-s). (3) Results: We found a significant association between the patients' perception of sleep abnormalities and scores of impaired independence, cognitive and motor performances. Specifically, sleep efficiency (PSQI-C4 subscores) and the use of sleep medications (PSQI-C6 subscores) seem to be more frequently associated with the severity of the disease progression. (4) Conclusion: sleep abnormalities represent an important part of the HD clinical profile and can impair patients' quality of life by affecting their level of independence, cognition performance and mental well-being.

Cognitive Reserve in Early Manifest Huntington Disease Patients: Leisure Time Is Associated with Lower Cognitive and Functional Impairment.

We focused on Cognitive Reserve (CR) in patients with early Huntington Disease (HD) and investigated whether clinical outcomes might be influenced by lifetime intellectual enrichment over time. CR was evaluated by means of the Cognitive Reserve Index questionnaire (CRIq), an internationally validated scale which includes three sections: education, working activity, and leisure time. The clinical HD variables were quantified at three different time points (baseline-t0, 1 year follow up-t1 and 2 years follow up-t2) as per the Unified Huntington's Disease Rating Scale (UHDRS), an internationally standardized and validated scale including motor, cognitive, functional and behavioral assays. Our sample consisted of 75 early manifest patients, withclinical stage scored according to the Total Functional Capacity (TFC) scale. Our correlational analysis highlighted a significant inverse association between CRIq leisure time (CRIq_LA) and longitudinal functional impairment (namely, the differential TFC score between t2 and t0 or ΔTFC) (p < 0.05), and the multidimensional progression of HD as measured by the composite UHDRS (cUHDRS, p < 0.01). CRIq_LA was significantly and positively associated with better cognitive performances at all time points (p < 0.05). Our results suggest that higher is the CRIq_LA, milder is the progression of HD in terms of functional, multidimensional and cognitive outcome.

"Spazio Huntington": Tracing the Early Motor, Cognitive and Behavioral Profiles of Kids with Proven Pediatric Huntington Disease and Expanded Mutations > 80 CAG Repeats.

The "Spazio Huntington-A Place for Children" program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children's Yale-Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials.

Arithmetic Word-Problem Solving as Cognitive Marker of Progression in Pre-Manifest and Manifest Huntington's Disease.

BACKGROUND: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington's disease (HD). OBJECTIVE: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations between arithmetic task performance and other neuropsychological tasks. METHODS: We collected data from a multicenter cohort of 165 HD gene-mutation carriers. The sample consisted of 31 premanifest participants: 16 far-from (>12 years estimated time to diagnosis; preHD-A) and 15 close-to (≤12 years estimated time to diagnosis; preHD-B), 134 symptomatic patients (early-mild HD), and 37 healthy controls (HC). We compared performance between groups and explored the associations between arithmetic word-problem solving and neuropsychological and clinical variables. RESULTS: Total arithmetic word-problem solving scores were lower in preHD-B patients than in preHD-A (p < 0.05) patients and HC (p < 0.01). Early-mild HD patients had lower scores than preHD patients (p < 0.001) and HC (p < 0.001). Compared to HC, preHD and early-mild HD participants made more errors as trial complexity increased. Moreover, arithmetic word-problem solving scores were significantly associated with measures of global cognition (p < 0.001), frontal-executive functions (p < 0.001), attention (p < 0.001) visual working memory (p < 0.001), mental rotation (p < 0.001), and confrontation naming (p < 0.05). CONCLUSION: Arithmetic word-problem solving is affected early in the course of HD and is related to deficient processes in frontal-executive and mentalizing-related processes.